CARDIOPROTECTIVE EFFECTS OF MONOPHOSPHORYL LIPID-A, A NOVEL ENDOTOXINANALOG, IN THE DOG

Objective: The major objective of the present study was to determine t he effects of a new endotoxin analogue, monophosphoryl lipid A (MLA), on myocardial infarct size in dogs. A second aim was to determine if p otential cardioprotective effects of MLA might be mediated via an enha ncement of antioxidant defence mechanisms. Methods: Barbiturate anaest hetised dogs were subjected to a 60 min left circumflex coronary arter y occlusion followed by 5 h reperfusion. Either of two different doses of MLA (30 and 100 mug-kg-1) or an equivalent volume of vehicle were given intravenously 24 h prior to the infarct experiments. Transmural myocardial blood flow was measured at 30 min of occlusion by the radio active microsphere technique and infarct size was determined at the en d of 5 h of reperfusion by triphenyltetrazolium staining. Tissue catal ase and myeloperoxidase activities were measured at 5 h of reperfusion as indices of antioxidant activity and neutrophil infiltration, respe ctively. Results: There were no significant differences between groups in systemic haemodynamic variables, myocardial oxygen demand, ischaem ic bed size, or coronary and collateral blood flow to the ischaemic re gion. However, administration of MLA produced a marked dose dependent reduction in myocardial infarct size: 19.8(SEM 3.7)% and 14.1(2.5)%, r espectively, v 32.7(2.9)% in the vehicle control group, p<0.05. Pretre atment with either 30 or 100 mug.kg-1 of MLA resulted in small increas es in tissue catalase activity in the non-ischaemic region of the hear t: 0.169(0.033) and 0.197(0.013) K.g-1, respectively, v 0.136(0.013) K .g-1 tissue in the control; however, the increases were not statistica lly significant by ANOVA. Myeloperoxidase activity in the border zone immediately adjacent to the infarct was markedly decreased in both MLA treated groups: MLA 30 mug.kg-1, 2.69(0.82); MLA 100 mug.kg-1, 2.49(0 .47), v control group, 5.81(1.20) units.g-1 tissue; p<0.05. Conclusion s: These data are the first to show a marked cardioprotective effect o f a lipid A derivative of endotoxin in an in vivo model of myocardial infarction. Although the mechanism responsible for the reduction in in farct size by MLA is unknown, a reduction in neutrophil migration at t he site of ongoing tissue injury, the border zone, may be partially re sponsible.